Abstract Despite the necessary role of dopamine in nicotine reinforcement, it is not sufficient to explain the complexity of addiction. Additional processes, particularly the ability of cues associated with nicotine exposure to develop control over behavior, are essential for ongoing drug seeking. Both human subjects and rodents experience reward-enhancement when exposed to nicotine. This has led to the idea that one of the primary factors driving nicotine addiction is its ability to potentiate the value of other appetitive stimuli and to accelerate cue-reward learning. In this proposal, we will investigate novel, circuit-level mechanisms that may underlie the ability of nicotine to potentiate responding for appetitive stimuli. We have discovered two, potentially interacting, microcircuits that increase responding for rewards and reward-paired cues, and have used proteomic, transcriptomic epigenomic approaches to identify intracellular pathways downstream of nAChRs that contribute to cellular and morphological plasticity following nicotine administration and could underlie potentiated cue- reward responding. Our Aims are to determine the role of a ventral tegmental area to ventral pallidum, and a basal forebrain to basolateral amygdala pathway, in enhanced cue-reward behavior, to determine whether these pathways interact, and to identify effects of nicotine on these circuits, as well as signaling pathways involved in neuronal plasticity that could maintain long-term changes in reward-related behaviors. Together, these proposed studies will go beyond initial steps of nicotine reward mediated through DA signaling to identify circuits and signaling pathways involved in the ability of nicotine to potentiate rewarding responses, processes that likely contribute to long-term susceptibility to nicotine addiction and relapse.